Design and synthesis of novel tetrabromophthalimide derivatives as potential tubulin inhibitors endowed with apoptotic induction for cancer treatment.

Although various approaches exist for treating cancer, chemotherapy continues to hold a prominent role in the management of this disease. Besides, microtubules serve as a vital component of the cellular skeleton, playing a pivotal role in the process of cell division making it an attractive target for cancer treatment. Hence, the scope of this work was adapted to design and synthesize new anti-tubulin tetrabromophthalimide hybrids (3-17) with colchicine binding site (CBS) inhibitory potential. The conducted in vitro studies showed that compound 16 displayed the lowest IC50 values (11.46 µM) at the FaDu cancer cell lines, whereas compound 17 exhibited the lowest IC50 value (13.62 µM) at the PC3 cancer cell line. However, compound 7b exhibited the lowest IC50 value (11.45 µM) at the MDA-MB-468 cancer cell line. Moreover, compound 17 was observed to be the superior antitumor candidate against all three tested cancer cell lines (MDA-MB-468, PC3, and FaDu) with IC50 values of 17.22, 13.15, and 13.62 µM, respectively. In addition, compound 17 showed a well-established upregulation of apoptotic markers (Caspases 3, 7, 8, and 9, Bax, and P53). Moreover, compound 17 induced downregulation of the antiapoptotic markers (MMP2, MMP9, and BCL-2). Furthermore, the colchicine binding site inhibition assay showed that compounds 15a and 17 exhibited particularly significant inhibitory potentials, with IC50 values of 23.07 and 4.25 µM, respectively, compared to colchicine, which had an IC50 value of 3.89 µM. Additionally, cell cycle analysis was conducted, showing that compound 17 could prompt cell cycle arrest at both the G0-G1 and G2-M phases. On the other hand, a molecular docking approach was applied to investigate the binding interactions of the examined candidates compared to colchicine towards CBS of the ß-tubulin subunit. Thus, the synthesized tetrabromophthalimide hybrids can be regarded as outstanding anticancer candidates with significant apoptotic activity.

Biological evaluation, docking studies, and in silico ADME prediction of some pyrimidine and pyridine derivatives as potential EGFRWT and EGFRT790M inhibitors.

Herein, a set of pyridine and pyrimidine derivatives were assessed for their impact on the cell cycle and apoptosis. Human breast cancer (MCF7), hepatocellular carcinoma (HEPG2), larynx cancer (HEP2), lung cancer (H460), colon cancers (HCT116 and Caco2), and hypopharyngeal cancer (FADU), and normal Vero cell lines were used. Compounds 8 and 14 displayed outstanding effects on the investigated cell lines and were further tested for their antioxidant activity in MCF7, H460, FADU, HEP2, HEPG2, HCT116, Caco2, and Vero cells by measuring superoxide dismutase (SOD), malondialdehyde content (MDA), reduced glutathione (GSH), and nitric oxide (NO) content. Besides, Annexin V-FITC apoptosis detection and cell cycle DNA index using the HEPG-2 cell line were established on both compounds as well. Furthermore, compounds 8 and 14 were assessed for their EGFR kinase (Wild and T790M) inhibitory activities, revealing eligible potential. Additionally, molecular docking, ADME, and SAR studies were carried out for the investigated candidates.

Design and synthesis of novel benzoazoninone derivatives as potential CBSIs and apoptotic inducers: In Vitro, in Vivo, molecular docking, molecular dynamics, and SAR studies.

Apparently, tubulin inhibitors binding to the colchicine-binding site (CBS) currently have outstanding attention for cancer treatment. So, a series of benzo[b]azonin-2-one derivatives having the same pharmacophoric features as colchicine binding site inhibitors (CBSIs) were synthesized targeting the CBS of ß-tubulin. The antiproliferative activities of the newly synthesized compounds were assessed against five different cancer cell lines; HepG-2, MCF-7, MDA-MB-231, HCT-116, and Caco-2. Compounds 7a and 7d displayed promising inhibitory activities against all tested cell lines. They were further estimated towards ß-tubulin at CBS along with colchicine (Col) as a reference drug. It was shown that the assessed candidates (7a and 7d) and Col exhibited CBSI activities of 5492, 3771, and 486c.p.m./mg protein, respectively, at a concentration of 10 µM. Furthermore, compound 7d was picked out to assess its effects on apoptosis and cell-cycle profile using Annexin V-FITC and PI staining assay. In addition, the apoptotic activity of 7d was investigated using gene expression analysis of apoptosis-related genes of P53, Bax, Caspases 3 and 9, and Bcl-2 in both treated and untreated cells. Moreover, compound 7d was further assessed through in vivo studies using solid Ehrlich carcinoma (SEC)-bearing mice. Furthermore, both molecular docking and molecular dynamics simulations (for 150 ns) were performed to investigate their mechanism of action as potential CBSIs and give more insights into the behavior of the examined candidates within the ß-tubulin subunit of the CBS. On the other hand, in silico ADMET studies were carried out to assess the pharmacokinetic features, drug/lead likeness, and toxicity parameters of the newly synthesized derivatives. Finally, to anticipate the possible changes in the antimitotic activities upon future structural modifications of the investigated compounds, a structure-activity relationship study (SAR) was accomplished.

Synthesis of novel cyanine dyes as antitumor agents.

In this study, some novel cyanine dyes, 1, 3, and 5-15, were synthesized by a one-pot step reaction of pyridinium salts 2 and/or 4 with benzenaminium salt 1. N-{[1-Chloro-3,4-dihydronaphthalen-2-yl)methylene]benzenaminium} chloride 1 was obtained by the reaction of α-tetralone with Vilsmeier-Haack reagent, followed by a mixture of an equimolar ratio of anilin/ethanol (1:1). All new cyanine dyes were evaluated in vitro for their anticancer activity against two cell lines, that is, HepG2 (human hepatocellular liver carcinoma) and MCF-7 (breast cancer). The obtained results were compared with human lung fibroblasts (WI-38) and Vero cells (derived from the kidney of an African green monkey) as normal cells. In particular, some of these compounds, 6, 9, 13, and 14, were found to be the most potent derivatives against all the cancer cell lines, without effect on the normal cells. According to the structure-activity relationship, compound 13 (IC50 = 8.8 µg/ml) exhibited a higher activity against HepG2 cells, as it contains the azo group and two phenyl rings and due to the presence of the π-conjugated system attached to the two pyridine rings. Compound 6 (IC50 = 8 µg/ml) exhibited a higher activity against MCF-7 cells, as it contains two chlorine atoms and the π-conjugated system of the pyridine rings.

Antimicrobial evaluation and docking study of some new substituted benzimidazole-2yl derivatives.

Benzimidazoles incorporated biologically active heterocycles such as quinoline, triazine-3-thione, thiazole and thiadiazole, were synthesized utilizing 2-acetylbenzimidazole as a building block. The structures of the newly synthesized benzimidazoles were assured by their spectral data (IR, 1H NMR, 13C- NMR and MS spectra). Most of the synthesized candidates were screened for their in vitro antimicrobial activity against Staphylococcus aureus, Escherichia coli, Bacillus pumilus and antifungal activity against (Saccharomyces cerevisiae). As a result, 2-(2-(1-(1H-benzo[d]imidazol-2-yl)ethylidene)hydrazineyl)-5-(furan-2-yl)-1,3,4-thiadiazole (14) had the most potent inhibitory activity against all tested bacteria with no antifungal inhibition. Furthermore, to gain insight into the mode of action of the synthesized compounds as antibacterial agents, docking studies were performed for the synthesized compounds in order to evaluate their activity as anti-bacterial agents. Virtual screening of the most promising compounds was performed against two bacterial proteins (DNA gyrase subunit B, and penicillin binding protein 1a) that are known targets for some antibiotics.

Synthesis, molecular docking and antimicrobial activity of new fused pyrimidine and pyridine derivatives.

Synthesis of some new heterocyclic ring systems incorporated pyrimidine and pyridine moieties starting from 1-(furan-2-yl)-3-(thiophen-2-yl) chalcone was achieved. The structure of the new compounds was interpreted by spectral studies and ESI-MS analysis. Antimicrobial investigations of the designated compounds were performed towards some harmful pathogenic microbes. Antimicrobial tests proved that compound 11 unveiled a greater antimicrobial activity than other designed compounds. Docking of compound 11 into active site of DNA gyrase B chain displayed binding-energy of -13.05 kJ mol-1 and distance at 3.18 Ao. Furthermore, docking investigation was approved for the goal compounds into DNA gyrase B chain and exhibiting binding energy extended from -13.05 to -20.48 kJ mol-1.

Synthesis, structural characterization, DFT calculations, molecular docking, and molecular dynamics simulations of a novel ferrocene derivative to unravel its potential antitumor activity.

In this article, we describe a set of subsequent five-steps chemical reactions to synthesize a ferrocene derivative named 1-(5-(diphenylphosphaneyl)cyclopenta-1,3-dien-1-yl)ethyl)imino)-1,3-dihydroisobenzofuran-5-yl)methanol (compound 10). Structural characterization of 10 and its intermediate products was also performed and reported to attest to their formation. A molecular docking study was performed to propose the novel synthesized ferrocene derivative (10) as a potential antitumor candidate targeting the mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1. The computed docking score of (10) at -9.50 kcal/mol compared to the native anticancer staurosporine at -8.72 kcal/mol postulated a promising anticancer activity. Also, molecular dynamics (MD) simulations were carried out for 500 ns followed by MM-GBSA-binding free energy calculations for both the docked complexes of ferrocene and staurosporine to give more deep insights into their dynamic behavior in physiological conditions. Furthermore, DFT calculations were performed to unravel some of the physiochemical characteristics of the ferrocene derivative (10). The quantum mechanics calculations shed the light on some of the structural and electrochemical configurations of (10) which would open the horizon for further investigation. HighlightsThe synthesis of a ferrocene derivative named 1-(5-(diphenylphosphaneyl)cyclopenta-1,3-dien-1-yl)ethyl)imino)-1,3-dihydroisobenzofuran-5-yl)methanol (compound 10) was described.Structural characterizations of ferrocene derivative (10) and its intermediate products were also performed.DFT calculations, molecular docking, molecular dynamics, and MM-GBSA calculations were carried out.Computational studies revealed the antitumor potential of ferrocene derivative (10) through targeting and inhibiting mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1.Communicated by Ramaswamy H. Sarma.

Synthesis and in vitro Anticancer Activity of Novel Heterocycles Utilizing Thiophene Incorporated Thioureido Substituent as Precursors.

Ethyl 2-(3-allylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (1) was used as a building block for synthesis of new heterocycles. Pyrimidine and thiazole moieties were achieved upon condensation of compound 1 with various reagents such as chloroacetic acid, dietyl malonate, ninhydrin, 2,3-epoxy-2,3-dihydro-1,4-naphthoquinone, and hydrazine hydrate. The structures of the newly synthesized compounds were confirmed using spectral measurements. The prepared products were evaluated for their anticancer activity against colon HCT-116 human cancer cell line. Compounds 6, 9, 10a, 11, 12, 15 have displayed potent activity.

Synthesis, Characterization, and Biochemical Impacts of Some New Bioactive Sulfonamide Thiazole Derivatives as Potential Insecticidal Agents against the Cotton Leafworm, Spodoptera littoralis.

A novel series of anticipated biologically active heterocyclic compounds, such as pyrazole, thiazole, pyridine, acrylamide, thiophene, triazolo[1,5-a]pyrimidine, imidazolidine, aminopyrazole, pyrazolo[5,1-c][1,2,4]triazine, triazolo[4,3-a]pyrimidine, benzo[4,5]imidazo[1,2-a]pyrimidine, pyrido[2',3':3,4]pyrazolo[5,1-c][1,2,4]triazine, isoxazole, benzo[4,5]imidazo[2,1-c][1,2,4]triazine, pyrimidine, pyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidine, pyrano[2,3-d]pyrimidine, and chromene derivatives, incorporating a sulfonamide-bearing thiazole moiety suitable to utilize as insecticidal agents were synthesized via a versatile, readily accessible cyanoacetanilide, 2-cyano-N-(4-(N-(thiazol-2-yl)sulfamoyl)phenyl)acetamide (1).The structures of the newly synthesized compounds were elucidated by IR, MS, 1H NMR, 13C NMR, distortionless enhancement by polarization transfer (DEPT), 1H-1H correlation spectroscopy (COSY), heteronuclear multiple bond correlation (HMBC), and heteronuclear single quantum coherence (HSQC) spectral analysis. Toxicological and biochemical parameters and biological aspects of the demonstrated compounds of the synthesized products against the cotton leafworm, Spodoptera littoralis, under laboratory conditions were also investigated. Regarding the determined LC50 and LC90 values, sulfonamides bearing a thiazole moiety, 16a, 8, 28, and 31b, showed the most potent toxic effects with LC50 values of 49.04, 62.66, 78.62, and 94.90 ppm, respectively, and toxicity index of 100%, 78.26%, 62.38%, and 51.68%, respectively.

Zinc Oxide Nanoparticle Synergizes Sorafenib Anticancer Efficacy with Minimizing Its Cytotoxicity.

Cancer, as a group, represents the most important cause of death worldwide. Unfortunately, the available therapeutic approaches of cancer including surgery, chemotherapy, radiotherapy, and immunotherapy are unsatisfactory and represent a great challenge as many patients have cancer recurrence and severe side effects. Methotrexate (MTX) is a well-established (antineoplastic or cytotoxic) chemotherapy and immunosuppressant drug used to treat different types of cancer, but its usage requires high doses causing severe side effects. Therefore, we need a novel drug with high antitumor efficacy in addition to safety. The aim of this study was the evaluation of the antitumor efficacy of zinc oxide nanoparticle (ZnO-NPs) and sorafenib alone or in combination on solid Ehrlich carcinoma (SEC) in mice. Sixty adult female Swiss-albino mice were divided equally into 6 groups as follows: control, SEC, MTX, ZnO-NPs, sorafenib, and ZnO-NPs+sorafenib; all treatments continued for 4 weeks. ZnO-NPs were characterized by TEM, zeta potential, and SEM mapping. Data showed that ZnO-NPs synergized with sorafenib as a combination therapy to execute more effective and safer anticancer activity compared to monotherapy as showed by a significant reduction (P < 0.001) in tumor weight, tumor cell viability, and cancer tissue glutathione amount as well as by significant increase (P < 0.001) in tumor growth inhibition rate, DNA fragmentation, reactive oxygen species generation, the release of cytochrome c, and expression of the apoptotic gene caspase-3 in the tumor tissues with minimal changes in the liver, renal, and hematological parameters. Therefore, we suggest that ZnO-NPs might be a safe candidate in combination with sorafenib as a more potent anticancer. The safety of this combined treatment may allow its use in clinical trials.